Synaptic Vesicle Docking: Sphingosine Regulates Syntaxin1 Interaction with Munc18

Abstract

Consensus exists that lipids must play key functions in synaptic activity but precise mechanistic information is limited. Acid sphingomyelinase knockout mice (ASMko) are a suitable model to address the role of sphingolipids in synaptic regulation as they recapitulate a mental retardation syndrome, Niemann Pick disease type A (NPA), and their neurons have altered levels of sphingomyelin (SM) and its derivatives. Electrophysiological recordings showed that ASMko hippocampi have increased paired-pulse facilitation and post-tetanic potentiation. Consistently, electron microscopy revealed reduced number of docked vesicles. Biochemical analysis of ASMko synaptic membranes unveiled higher amounts of SM and sphingosine (Se) and enhanced interaction of the docking molecules Munc18 and syntaxin1. In vitro reconstitution assays demonstrated that Se changes syntaxin1 conformation enhancing its interaction with Munc18. Moreover, Se reduces vesicle docking in primary neurons and increases paired-pulse facilitation when added to wt hippocampal slices. These data provide with a novel mechanism for synaptic vesicle control by sphingolipids and could explain cognitive deficits of NPA patients.

High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

“…8 In mice lacking ASM (acid sphingomyelinase knockout mice, ASMko), which are a model for NPA, 9 gradual accumulation of SM occurs in brain lysosomes and at the plasma and synaptic membranes of neurons. 10,11 Here we have analyzed the autophagy-lysosomal systems in the brain of ASMko mouse and in fibroblasts from NPA patients. Our work demonstrates the existence of autophagy alterations in this disease, defines SM excess as a key determinant in these alterations and proposes strategies to revert them.…”

Recruitment of sphingosine kinase to presynaptic terminals by a conserved muscarinic signaling pathway promotes neurotransmitter release

“…The generation of S1P by SphKs elicits the secretion of neurotransmitters from a variety of neurons and neurosecretory cells (Alemany et al 2001;Brailoiu et al 2002;Pan et al 2006;Kajimoto et al 2007;Olivera 2008) and modulates sensory neuron excitability (Nicol 2008). In addition, SPH has been shown to have functions in synaptic vesicle (SV) exocytosis and SV cycling (Rohrbough et al 2004;Nicol 2008;Camoletto et al 2009;Darios et al 2009). Furthermore, SphK1 is concentrated at presynaptic terminals in neuronal cultures (Kajimoto et al 2007).…”

Monogenic neurological disorders of sphingolipid metabolism

“…SM accumulation is seen in total brain extracts (along with GM2 and GM3) and in myelin [49,50]. Sphingosine and sphingosylphosphocholine levels are also increased in total brain extracts of deficient mice [51]. At the cellular level, the SL content of neuronal and glial cell membranes is modified.…”

“…At the cellular level, the SL content of neuronal and glial cell membranes is modified. Lysosomal but also non-lysosomal membranes, including synaptic membranes, are enriched in SM and sphingosine [49][50][51]. This change of lipid membrane composition is thought to alter cell signaling (by affecting plama membranes microdomains), neuronal polarization, calcium homeostasis, synaptic plasticity, myelin production and immune response (for a review, see [52]).…”